Abstract |
The cellular bromodomain protein Brd4 is a major interacting partner of the papillomavirus (PV) E2 protein. Interaction of E2 with Brd4 contributes to viral episome maintenance. The E2-Brd4 interaction also plays an important role in repressing viral oncogene expression from the integrated viral genome in human PV (HPV)-positive cancer cells. However, the underlying mechanism is not clearly understood. In host cells, Brd4 recruits positive transcription elongation factor b ( P-TEFb) to stimulate RNA polymerase II phosphorylation during cellular and viral gene expression. P-TEFb associates with the C terminus of Brd4, which largely overlaps with the E2 binding site on Brd4. In this study, we demonstrate that E2 binding to Brd4 inhibits the interaction of endogenous Brd4 and P-TEFb. P-TEFb is essential for viral oncogene E6/E7 transcription in both HeLa and CaSki cells that contain integrated HPV genomes. E2 binding to Brd4 abrogates the recruitment of P-TEFb to the integrated viral chromatin template, leading to inactivation of P-TEFb and repression of the viral oncogene E6/E7. Furthermore, dissociation of the Brd4-P-TEFb complex from the integrated viral chromatin template using a Brd4 bromodomain dominant-negative inhibitor also hampers HPV E6/E7 oncogene expression. Our data support that Brd4 recruitment of P-TEFb to the viral chromatin template is essential for viral oncogene expression. Abrogation of the interaction between P-TEFb and Brd4 thus provides a mechanism for E2-mediated repression of the viral oncogenes from the integrated viral genomes in cancer cells.
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Authors | Junpeng Yan, Qing Li, Sam Lievens, Jan Tavernier, Jianxin You |
Journal | Journal of virology
(J Virol)
Vol. 84
Issue 1
Pg. 76-87
(Jan 2010)
ISSN: 1098-5514 [Electronic] United States |
PMID | 19846528
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- BRD4 protein, human
- Cell Cycle Proteins
- DNA-Binding Proteins
- E2 protein, Human papillomavirus type 16
- E6 protein, Human papillomavirus type 16
- Nuclear Proteins
- Oncogene Proteins, Viral
- Papillomavirus E7 Proteins
- Repressor Proteins
- Transcription Factors
- oncogene protein E7, Human papillomavirus type 16
- Positive Transcriptional Elongation Factor B
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Topics |
- Alphapapillomavirus
(genetics)
- Cell Cycle Proteins
- Cell Line
- Cell Line, Tumor
- DNA-Binding Proteins
(physiology)
- Genes, Viral
- Humans
- Nuclear Proteins
(metabolism)
- Oncogene Proteins, Viral
(antagonists & inhibitors, genetics, physiology)
- Papillomaviridae
(chemistry, physiology)
- Papillomavirus E7 Proteins
- Positive Transcriptional Elongation Factor B
(antagonists & inhibitors, genetics, metabolism)
- Promoter Regions, Genetic
- Protein Binding
- Repressor Proteins
(antagonists & inhibitors, genetics)
- Transcription Factors
(metabolism)
- Transcription, Genetic
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